Orexin (hypocretin) neuropeptides are derived from a single gene (HCRT) encoding prepro-orexin that is processed into the mature 33 amino acid orexin A (OX-A) and orexin B (OX-B) peptides (Wong et al., Gen Comp Endocrinol, 2011, 171, 124-130). Both neuropeptides have overlapping endogenous specificity for two related G-protein coupled receptors found throughout mammals, orexin 1 and orexin 2 receptors (OX1R and OX2R, respectively) (Scammell and Winrow, Ann Rev Pharmacol Toxicol, 2011, 51, 243-266). OX-A has activity toward both OX1R and OX2R having binding affinities of 20 and 38 nM, respectively, while OX-B is relatively specific for OX2R, exhibiting 36 nM affinity relative to 420 nM activity toward OX1R (Sakurai et al., Cell, 1998, 92, 573-585). Orexin secreting neurons originate from the lateral and posterior areas of the hypothalamus and project to multiple brain regions to affect arousal and vigilance state changes associated with sleep/wake cycles (Scammell and Winrow, Ann Rev Pharmacol Toxicol, 2011, 51, 243-266), but also have the potential to influence behavior and physiology including feeding, metabolism and gastrointestinal function (Sakurai et al., Cell, 1998, 92, 573-585; Tsujino and Sakurai, Pharmacol Rev, 2009, 61, 162-176), reward pathways associated with addiction, learning and memory (Harris, et al., Trends Neurosci., 2006, 29, 571-577), anxiety behavior modulation (Suzuki et al., Brain Res, 2005, 1044, 116-121), depression and mood (Scott et al., Behav Brain Res, 2011222, 289-294) and the modulation of migraine and nociception (Akerman et al., Nat Rev Neurosci., 2011, 12, 570-84; Mobarakeh et al., Peptides, 2005, 26, 767-777).